Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction

Abstract

The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…First, inflammation can influence phosphorylation of BDNF's receptor (TrkB), interfering with BDNF signaling (Cortese et al, 2011); and subsequent intracellular signal transduction can be impaired by inflammatory cytokines such as IL-1 (Tong et al, 2008). Both processes could impact depression more in those who start out with low BDNF.…”

“…Inflammatory cytokines can decrease BDNF signaling (Cortese et al, 2011;Tong et al, 2008), as can lipopolysaccharide injections (Guan and Fang, 2006). Therefore, in addition to IFN-a's effects on serotonin , dopamine (Felger et al, 2007), glutamate (Raison et al, 2010b), and the hypothalamic-pituitary-adrenal axis (Raison et al, 2010a), a decrease in BDNF may ultimately be the reason for the development of depression during IFN-a treatment.…”

Interleukin-1β interferes with signal transduction induced by neurotrophin-3 in cortical neurons

“…IL-1β levels are elevated in the brain with aging and even more so in neurodegenerative disorders, such as AD. We observed that IL-1β, under conditions when it does not compromise neuronal viability, interferes with BDNF signaling by reducing activation of the docking proteins that convey the signal from the activated Trk receptors to the Ras/MAPK and PI3-K/Akt pathways, and thus elicits a type of neurotrophin resistant state (Tong et al 2007). The functional consequences were severe, as neuronal vulnerability was increased.…”

“…Recently we examined the effect of the proinflammatory cytokine IL-1β on BDNF signaling and function (Tong et al 2007). IL-1β levels are elevated in the brain with aging and even more so in neurodegenerative disorders, such as AD.…”

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AbstractIt was previously observed that IL-1β interferes with BDNF-induced TrkB-mediated signal transduction and protection of cortical neurons from apoptosis evoked by deprivation from trophic support (Tong et al 2007). Here we investigated whether the effect of the cytokine on neurotrophin signaling is more general.

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